HPV Virus Medical Research

Saqi A, Pasha TL, McGrath CM, Yu GH, Zhang P, Gupta P. Department of Pathology and Laboratory Medicine, University of Pennsylvania Health System, Philadelphia, Pennsylvania 19104, USA.

Human papillomavirus (HPV) is recognized as a causal agent for cervical carcinomas. Assimilation of HPV oncogenes E6 and E7 into the host DNA promotes upregulation of cyclin dependent kinase inhibitor (CDKI) p16(INK4A), detectable by monoclonal antibody in the developing cervical cancer cells. The aim of this study was to 1) develop a protocol for p16(INK4A) immunocytochemical staining on SurePath preparations, and 2) determine its utility as an HPV marker on a spectrum of cervical reactive and neoplastic lesions. Seventy-two specimens consisting of 28 nonneoplastic/nondysplastic cases (NN), one reactive glandular cells (RGC), 27 low-grade squamous intraepithelial lesions (LSIL), 10 high-grade squamous intraepithelial lesions (HSIL), one squamous cell carcinoma (SCCA), four atypical glandular cells (AGUS), and two adenocarcinomas (ADCA) were reprepped by SurePath and antibody to p16(INK4A) applied at 1:100 dilution using the Dako Envision + System on the Dako Autostainer. Expression of p16(INK4A) within the nucleus principally and cytoplasm of at least 10-15 cells was considered positive. All initial Papanicolaou-stained discrepant cases (p16(INK4A) positivity of NN and RGC cases and lack of reactivity in LSIL, HSIL, and AGUS) were reviewed. Nine of ten (90%) HSIL, one (100%) SCCA, 21/27 (78%) LSIL, and some reactive and inflammatory specimens demonstrated the presence of p16(INK4A). Reevaluation of discrepant cases revealed that several were underinterpreted (four NN were LSIL, one RGC was AGUS) or overinterpreted (one LSIL was NN). Following reassessment, false-positive staining was present in only 1/25 (1.4%) NN. Six of 30 (20%) LSIL lacked p16(INK4A) positivity. One of 10 (10%) HSIL had no staining. Two of four AGUS did not react with p16(INK4A) antibody. Both SCCA (1) and ADCA (2) had positive expression. This study confirms the intimate relationship between p16(INK4A) and HPV cytopathic effect. The p16(INK4A) immunocytochemical stain can be applied to liquid-based cervical preparations. This technique offers a more objective approach to deciphering "gray areas" of gynecologic cytopathology. Copyright 2002 Wiley-Liss, Inc.

Publication Types:
• Validation Studies

Riethdorf L, Riethdorf S, Lee KR, Cviko A, Loning T, Crum CP. Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.

Adenocarcinoma in situ (ACIS) is the precursor of cervical adenocarcinoma (ACs), and its distinction from benign but morphologically atypical glandular epithelium may be difficult. The cyclin-dependent kinase inhibitor p16(ink4) is expressed in cervical squamous cell carcinomas, their precursors, and cervical ACs, and there is a strong relationship between p16 expression and the presence of human papillomavirus (HPV)-encoded E6/E7 transcription. This study analyzed 95 cases of benign and premalignant cervical glandular ACIS lesions for p16 antigen and the proliferative marker Ki-67; HPV E6/E7 transcripts were detected by RNA/RNA in situ hybridization. HPV 16 or 18 E6/E7 transcription and strong, diffuse p16 positivity were detected only in ACIS lesions. A high and moderate Ki-67 index was observed in 76% and 22% of ACIS, respectively. Thirty-three of 36 microglandular change, tubal, atypical tubal, and endometrial-type epithelia scored negative or weakly positive for p16. Distribution of staining in 3 strongly positive cases was heterogeneous. The diffuse distribution of p16 immunostaining in HPV16/18-positive glandular neoplasms supports a strong association with HPV infection and indicates that this biomarker may discriminate ACIS from its benign mimics. However, this distinction requires attention to staining distribution because p16 is focally expressed in tubal-endometrial epithelia and diffusely expressed in endometrium, indicating that in some cases the use of other biomarkers, such as Ki-67, may be necessary. Because endometrial glandular epithelia may also express p16, the diagnostic application of p16 immunohistochemistry to cytological samples is uncertain. Copyright 2002, Elsevier Science (USA). All rights reserved.

Rev Invest Clin. 2002 Jul-Aug;54(4):299-306.

High-risk human papilloma virus and cervical intraepithelial neoplasia in women at 2 hospitals in Mexico City.

HPV Virus Medical Research - Article in Spanish

OBJECTIVE: To determine the high risk HPV (HR-HPV) association with Cervical Intraepithelial Neoplasia (CIN) in women of two Dysplasia Clinics in Mexico City. MATERIAL AND METHODS: Prolective case-control study was done. Women with and without security affiliation attended in Instituto Mexicano del Seguro Social (Hospital 1) and Hospital General de Mexico (Hospital 2) were included in the study. Cases were women with histopathologic diagnosis of CIN and controls were women with negative dysplasia in cytologic study (Pap). Information was obtained by direct interview. HR-HPV was determined by Hybrid Capture II assay, in cervical samples. Bivariate and logistic regression analysis was done. RESULTS: One hundred and two cases and 192 controls from Hospital 1 and 89 cases and 66 controls from Hospital 2 were included. 83.3% and 77.3% of women from Hospital 1 and 2 respectively were positive to HR-HPV. The association HR-HPV and CIN in Hospital 1 was ORa = 40.6, C.I. 95% = 17-96.8; while in Hospital 2 there was not association. Age was an effect modifier in the HR-HVP and CIN association, in Hospital 1. It was observed a correlation between viral load and CIN degree. CONCLUSIONS: The HR-HPV infection frequency in controls and CIN I was higher than the reported in other studies. Age was a modifier in the HR-HPV association and CIN. In dysplasia clinics without medical referral system of patients is possible to observe similar risk factors to cervical cancer.

Publication Types:
• Multicenter Study

Ginekol Pol. 2002 Oct;73(10):856-60.

The coexistence of vulvovaginal warts and cervical dysplasia with HPV infection and cervicitis.

HPV Virus Medical Research - Article in Polish

We present a case of 30-year old female patient with persistent cervicitis and vulvovaginal warts. In the course of diagnosis were found cervical dysplasia and a HPV infection type 6 and 11. In therapy we applied antibiotics, chemical therapy of the warts, laser vaporization of the warts, laser conisation, immunotherapy. Three years' intensive therapy didn't lead to satisfactory results. Finally hysterectomy led to the acceptable therapeutical effect.

Publication Types:
• Case Reports

Eur J Cancer. 2002 Nov;38(17):2229-42.

New markers for cervical dysplasia to visualise the genomic chaos created by aberrant oncogenic papillomavirus infections.

von Knebel Doeberitz M. Division of Molecular Pathology, Department of Pathology, School of Medicine, University of Heidelberg, Im Neuenheimer Feld 220, D-69120, Heidelberg, Germany. knebel@med.uni-heidelberg.de

Extensive research over the past 20 years provided strong evidence that persistent infections with high risk type human papillomaviruses (HR-HPVs) cause cervical cancer. However, depending on their age, more than 20% of normal women are infected with these viruses and only very few develop clinically relevant dysplastic lesions or even cancer. During an acute HPV infection, expression of viral genes, in particular the viral E6 and E7 oncogenes is restricted to differentiated epithelial cells, which lost the capability to replicate their genomes and are therefore at no further risk for acquiring functionally relevant mutations upon genotoxic damage. High grade cervical dysplasia, however, is initiated by deregulated expression of viral oncogenes in replicating epithelial stem cells. Here, the E6-E7 gene products submerge control of the cell cycle and mitotic spindle pole formation through complex interactions with various cellular protein complexes and induce severe chromosomal instability. The detailed molecular analysis of these interactions allowed to define new biomarkers for dysplastic cervical cells. E7 for example induces increasing expression of the cyclin dependent kinase inhibitor p16(ink4a) in dysplastic cells. This can be used to identify dysplastic cells in histological slides, cytological smears or samples taken for biochemical analyses with an yet unmet fidelity. Detection of specific viral mRNAs derived from integrated HPV genomes in advanced precancers can be used to identify lesions with a particularly high risk for progression into invasive carcinomas (APOT assay). These new markers will result in a modified classification of cervical precancers and improved screening assays. Here, we review the basic concept and potential clinical applications of these new developments.

Publication Types:
• Review
• Review, Tutorial

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